Amelioration of mercury nephrotoxicity after pharmacological manipulation of organic anion transporter 1 (Oat1) and multidrug resistance-associated protein 2 (Mrp2) with furosemide

ABSTRACTEntecavir (ETV) is a first-line antiviral agent for the treatment of chronic hepatitis B virus infection. Renal excretion is the major elimination path of ETV, in which tubular secretion plays the key role. However, the secretion mechanism has not been clarified. We speculated that renal transporters mediated the secretion of ETV. Therefore, the aim of our study was to elucidate which transporters contribute to the renal disposition of ETV. Our results revealed that ETV (50 μM) remarkably reduced the accumulation of probe substrates in MDCK cells stably expressing human multidrug and toxin efflux extrusion proteins (hMATE1/2-K), organic cation transporter 2 (hOCT2), and carnitine/organic cation transporters (hOCTNs) and increased the substrate accumulation in cells transfected with multidrug resistance-associated protein 2 (hMRP2) or multidrug resistance protein 1 (hMDR1). Moreover, ETV was proved to be a substrate of the above-described transporters. In transwell studies, the transport of ETV in MDCK-hOCT2-hMATE1 showed a distinct directionality from BL (hOCT2) to AP (hMATE1), and the cellular accumulation of ETV in cells expressing hMATE1 was dramatically lower than that of the mock-treated cells. The accumulation of ETV in mouse primary renal tubular cells was obviously affected by inhibitors of organic anion transporter 1/3 (Oat1/3), Oct2, Octn1/2, and Mrp2. Therefore, the renal uptake of ETV is likely mediated by OAT1/3 and OCT2 while the efflux is mediated by MATEs, MDR1, and MRP2, and OCTN1/2 may participate in both renal secretion and reabsorption.

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Expression of γ-glutamylcysteine synthetase (γ-GCS) and multidrug resistance-associated protein (MRP), but not human canalicular multispecific organic anion transporter (cMOAT), genes correlates with exposure of human lung cancers to platinum drugs

British Journal of Cancer ◽

10.1038/bjc.1998.181 ◽

1998 ◽

Vol 77 (7) ◽

pp. 1089-1096 ◽

Cited By ~ 50

Author(s):

T Oguri ◽

Y Fujiwara ◽

T Isobe ◽

O Katoh ◽

H Watanabe ◽

...

Keyword(s):

Multidrug Resistance ◽

Human Lung ◽

Organic Anion ◽

Organic Anion Transporter ◽

Platinum Drugs ◽

Lung Cancers ◽

Anion Transporter ◽

Glutamylcysteine Synthetase

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Interactions of 172 plant extracts with human organic anion transporter 1 (SLC22A6) and 3 (SLC22A8): a study on herb-drug interactions

PeerJ ◽

10.7717/peerj.3333 ◽

2017 ◽

Vol 5 ◽

pp. e3333 ◽

Cited By ~ 10

Author(s):

Hang Lu ◽

Zhiqiang Lu ◽

Xue Li ◽

Gentao Li ◽

Yilin Qiao ◽

...

Keyword(s):

Drug Interactions ◽

Plant Extracts ◽

Organic Anion ◽

Organic Anion Transporter ◽

Hek293 Cells ◽

Pharmacokinetic Parameters ◽

Renal Elimination ◽

Juncus Effusus ◽

Anion Transporter

BackgroundHerb-drug interactions (HDIs) resulting from concomitant use of herbal products with clinical drugs may cause adverse reactions. Organic anion transporter 1 (OAT1) and 3 (OAT3) are highly expressed in the kidney and play a key role in the renal elimination of substrate drugs. So far, little is known about the herbal extracts that could modulate OAT1 and OAT3 activities.MethodsHEK293 cells stably expressing human OAT1 (HEK-OAT1) and OAT3 (HEK-OAT3) were established and characterized. One hundred seventy-two extracts from 37 medicinal and economic plants were prepared. An initial concentration of 5 µg/ml for each extract was used to evaluate their effects on 6-carboxylfluorescein (6-CF) uptake in HEK-OAT1 and HEK-OAT3 cells. Concentration-dependent inhibition studies were conducted for those extracts with more than 50% inhibition to OAT1 and OAT3. The extract ofJuncus effusus, a well-known traditional Chinese medicine, was assessed for its effect on thein vivopharmacokinetic parameters of furosemide, a diuretic drug which is a known substrate of both OAT1 and OAT3.ResultsMore than 30% of the plant extracts at the concentration of 5 µg/ml showed strong inhibitory effect on the 6-CF uptake mediated by OAT1 (61 extracts) and OAT3 (55 extracts). Among them, three extracts for OAT1 and fourteen extracts for OAT3 were identified as strong inhibitors with IC50values being <5 µg/ml.Juncus effususshowed a strong inhibition to OAT3in vitro, and markedly altered thein vivopharmacokinetic parameters of furosemide in rats.ConclusionThe present study identified the potential interactions of medicinal and economic plants with human OAT1 and OAT3, which is helpful to predict and to avoid potential OAT1- and OAT3-mediated HDIs.

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Differential expression of multidrug resistance (mdr) and canalicular multispecific organic anion transporter (cMOAT) genes following extrahepatic biliary obstruction in rats

IUBMB Life ◽

10.1080/15216549800201462 ◽

1998 ◽

Vol 44 (3) ◽

pp. 443-452

Author(s):

Tatehiro Kagawa ◽

Norihito Watanabe ◽

Masahiro Sato ◽

Atsushi Nakano ◽

Yasuhiro Nishizaki ◽

...

Keyword(s):

Multidrug Resistance ◽

Differential Expression ◽

Biliary Obstruction ◽

Organic Anion ◽

Organic Anion Transporter ◽

Anion Transporter ◽

Extrahepatic Biliary Obstruction

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Direct Evidence that Saquinavir Is Transported by Multidrug Resistance-Associated Protein (MRP1) and Canalicular Multispecific Organic Anion Transporter (MRP2)

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.11.3456-3462.2002 ◽

2002 ◽

Vol 46 (11) ◽

pp. 3456-3462 ◽

Cited By ~ 92

Author(s):

Gregory C. Williams ◽

Angela Liu ◽

Gregory Knipp ◽

Patrick J. Sinko

Keyword(s):

Multidrug Resistance ◽

Cell Lines ◽

Direct Evidence ◽

Organic Anion ◽

Lethal Dose ◽

Organic Anion Transporter ◽

Cell Monolayers ◽

Directed Transport ◽

Anion Transporter ◽

Efflux Ratio

ABSTRACT To determine if saquinavir mesylate (saquinavir) is a substrate of human multidrug resistance-associated protein 1 (hMRP1 [ABCC1]) or hMRP2 (cMOAT, or ABCC2), MDCKII cells that overexpress either hMRP1 (MDCKII-MRP1) or hMRP2 (MDCKII-MRP2) were used to investigate saquinavir's cytotoxicity and transport in comparison with those of control MDCKII wild-type (MDCKII/wt) cells. Cytotoxicity was assessed with the mitochondrial marker MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium], and saquinavir transport was measured directly through the cell monolayers. GF120918 (an inhibitor of P glycoprotein, but not of the MRP family) and MK-571 (an MRP family inhibitor) were used to delineate the specific contributions of these transporters to saquinavir cytotoxicity and transport. In the presence of GF120918 and increasing saquinavir concentrations, the MDCKII-MRP1 (50% lethal dose [LD50] = 10.5 μM) and MDCKII-MRP2 (LD50 = 27.1 μM) cell lines exhibited statistically greater viability than the MDCKII/wt cells (LD50 = 7.8 μM). Saquinavir efflux was directional, not saturable, and was inhibited by MK-571 (35 and 75 μM) in all cell lines. The ratios of saquinavir (3 μM) basolateral to apical permeability (i.e., efflux ratios) for the MDCKII/wt, MDCKII-MRP1, and MDCKII-MRP2 cell monolayers were 2.6, 1.8, and 6.8, respectively. The MDCKII-MRP1 cells have a significantly reduced saquinavir efflux ratio relative to MDCKII/wt cells, due to basolaterally directed transport by hMRP1 competing with endogenous, apically directed canine MRP2. The MDCKII-MRP2 cells have a significantly increased saquinavir efflux ratio relative to MDCKII/wt cells, due to the additive effects of the apically directed transport by hMRP2 and endogenous MRP2. Collectively, the cytotoxicity and transport results provide direct evidence that saquinavir is transported by MRP1 and MRP2.

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